Project Summary The goal of this K23 application is to provide a tailored program of mentored research training for Dr. Keenan Walker, a neuropsychologist in the Department of Neurology at Johns Hopkins University School of Medicine. Over the last several years, Dr. Walker has positioned himself to become a leader in the field of Alzheimer?s disease research, with particular expertise in understanding the mechanistic connection between aberrant immune functioning, cognitive decline, and Alzheimer?s disease. Dr. Walker seeks a Career Development Award to obtain mentored research experience, new skills, and content knowledge that are critical to advancing his career as an independent investigator. The research plan outlined in this application leverages existing data from the Atherosclerosis Risk in Communities (ARIC) study with novel methods to examine the association of discrete systemic- and neuro-inflammatory pathways with components of Alzheimer?s disease pathogenesis in a community sample of non-demented older adults. There is currently no consensus as to whether neuroinflammation takes on a protective or pathological role in the preclinical and mild cognitive impairment (MCI) phase of Alzheimer?s disease. Relatedly, it is unclear whether systemic pro- and anti- inflammatory signaling may influence the activation of neuroinflammatory pathways, or the progression of ?- amyloid (A?) deposition. The proposed research uses stored blood specimens to determine whether systemic pro- and anti-inflammatory signaling is associated with longitudinal change in A? deposition (as measured by PET), MRI-defined neurodegeneration, and cognitive decline in a large group (N=1,000) of non-demented older adults within the ARIC cohort (Aim 1). Using novel methods to measure the contents of astrocyte-derived exosomes (ADEs) in a subset of participants (N=500), this study will also determine whether the activity of discrete astrocytic neuroinflammatory pathways (e.g., complement, and cytokine signaling) relates to subsequent A? accumulation, neurodegeneration, and cognitive decline (Aim 2). Lastly, this study will examine how these markers of systemic- and neuro-inflammation relate to 18-kDa translocator protein (TSPO) PET measures of microglial activation in a small sample of adults with MCI (Aim 3). This K23 will support Dr. Walker in pursuit of his training goals, which include (1) acquiring the skills and knowledge necessary to use exosomes for the study of molecular pathways relevant to Alzheimer?s disease, (2) gaining proficiency with PET imaging as a research tool for the study of A? deposition and neuroinflammation, and (3) developing an advanced understanding of relevant immunological and neuro-immunological principles. To achieve these training goals, Dr. Walker has established a multidisciplinary team of world-renowned mentors and collaborators with expertise in Alzheimer disease, neuroimmunology, aging biology, and molecular imaging. This training plan will provide Dr. Walker with the mentored experiences and expertise necessary to excel as an independent investigator conducting patient-oriented dementia and cognitive aging research.